4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1,2,2-trimethyl-piperazine and the salts thereof, pharmaceutical compositions containing these salts and the medical use thereof, including treatment of schizophrenia or other diseases involving psychotic symptoms, is disclosed in WO2005/016900. 4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1,2,2-trimethyl-piperazine is hereinafter referred to as Compound (I)
Compound (I) is also known as Zicronapine.
EP 638 073 covers a group of trans isomers of 3-aryl-1-(1-piperazinyl)indanes substituted in the 2- and/or 3-position of the piperazine ring. The compounds are described as having high affinity for dopamine D1 and D2 receptors and the 5-HT2 receptor and are suggested to be useful for treatment of several diseases in the central nervous system, including schizophrenia.
Compound (I) above has been described by Bøgesø et al. in J. Med. Chem., 1995, 38, page 4380-4392, in the form of the fumarate salt, see table 5, compound (−)-38. This publication concludes that the (−)-enantiomers of compound 38 is a potent D1/D2 antagonists showing some D1 selectivity in vitro. The compound is also described as a potent 5-HT2 antagonist. It is also mentioned that the compound does not induce catalepsy in rats.
The aetiology of schizophrenia is not known, but the dopamine hypothesis of schizophrenia formulated in the early 1960s, has provided a theoretical framework for understanding the biological mechanisms underlying this disorder (Carlsson, Am. J. Psychiatry 1978, 135, 164-173). In its simplest form, the dopamine hypothesis states that schizophrenia is associated with a hyperdopaminergic state, a notion which is supported by the fact that all antipsychotic drugs on the market today exert some dopamine D2 receptor antagonism (Seeman Science and Medicine 1995, 2, 28-37). However, whereas it is generally accepted that antagonism of dopamine D2 receptors in the limbic regions of the brain plays a key role in the treatment of positive symptoms of schizophrenia, the blockade of D2 receptors in striatal regions of the brain causes extrapyramidal symptoms (EPS). As described in EP 638 073 a profile of mixed dopamine D1/D2 receptor inhibition has been observed with some so-called “atypical” antipsychotic compounds, in particular with clozapine (8-chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4] diazepine), used in treatment of schizophrenic patients.
Further, selective D1 antagonists have been connected to treatment of sleep disorders and alcohol abuse (D. N. Eder, Current Opinion in Investigational Drugs, 2002 3(2):284-288).
Dopamine may also play an important role in the aetiology of affective disorders (P. Willner, Brain. Res. Rev. 1983, 6, 211-224, 225-236 and 237-246; Bøgesø et al, J. Med. Chem., 1985, 28, 1817-1828).
In EP 638 073 is described how compounds having affinity for 5-HT2 receptors, in particular 5-HT2A receptor antagonists, have been suggested for treatment of different diseases, such as schizophrenia including the negative symptoms in schizophrenic patients, depression, anxiety, sleep disturbance, migraine attacks and neuroleptic-induced parkinsonism. 5-HT2A receptor antagonism has also been suggested to reduce the incidence of extrapyramidal side effects induced by classical neuroleptics (Balsara et al. Psychopharmacology 1979, 62, 67-69).
Psychotic patients, and in particular schizophrenic patients, are often unwilling or unable to take their medication regularly; several studies have shown that a less frequent dosing results in higher degree of compliance and thus eventually better treatment of the patients. Therefore there is an unmet need for long acting preparations of antipsychotic medicine. In particular there is a need for long acting preparations of antipsychotic medicine in non-invasive form that represent an alternative to intra muscular depot formulations in order to make change in dosing regime, frequency of medication or type of medication, more flexible.